EP2041132A2 - Neue verbindungen - Google Patents
Neue verbindungenInfo
- Publication number
- EP2041132A2 EP2041132A2 EP07787138A EP07787138A EP2041132A2 EP 2041132 A2 EP2041132 A2 EP 2041132A2 EP 07787138 A EP07787138 A EP 07787138A EP 07787138 A EP07787138 A EP 07787138A EP 2041132 A2 EP2041132 A2 EP 2041132A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- membered
- tetrahydro
- imidazo
- pyridin
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to new 4-heterocycloalkylpyrimidines of general formula (1)
- the present invention relates to compounds of general formula (1)
- R 1 denotes 8-12 membered heterocycloalkyl, optionally substituted by one or more identical or different R 4
- R 2 denotes a group selected from among C ⁇ -isaryl, 3-8 membered heterocycloalkyl and 5- 14 membered heteroaryl, substituted by one or more identical or different R 4
- R 3 denotes a group selected from among halogen, -CN, , -NR f R f , -OR f , -C(O)R f , -SR f , -S(O)R f , -S(O) 2 R f , Ci -4 alkyl, Ci -4 haloalkyl, C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl, and R 4 denotes a group selected from among R a , R b and R a substituted by one or more identical or different R c and/or R
- each R d independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R e and/or R f selected from among
- the invention relates to compounds of general formula (1), wherein X denotes N.
- the invention relates to compounds of general formula (1), wherein R 3 denotes a group selected from among halogen, -NR f R f , -OR f , -C(O)R f , C 1-4 alkyl, and C ⁇ .scycloalkyl.
- the invention relates to compounds of general formula (1), wherein R 2 denotes a group selected from among phenyl and 5-12 membered heteroaryl.
- Q denotes 5, 6 or 7 membered heterocycloalkyl
- R 2 , R 3 and R 4 are as hereinbefore defined.
- the invention in another aspect relates to compounds of general formula (1), wherein R 2 denotes phenyl substituted by a 5-6 membered heterocycloalkyl, which may optionally be substituted by one or more identical or different R c and/or R b .
- R 2 denotes phenyl substituted by -C(O)NR 0 R 0 .
- (C2) In another aspect the invention relates to compounds of general formula (1), wherein R 3 denotes methoxy. All the above mentioned aspects (Al) and (A2) for R 1 , (Bl) to (B6) for R 2 and (Cl) and (C2) for R 3 may be combined with one another as desired.
- the invention relates to compounds of general formula (1) or (IA), or the pharmaceutically effective salts thereof, for use as pharmaceutical compositions.
- the invention relates to compounds of general formula (1) or (IA), or the pharmaceutically effective salts thereof, for preparing a pharmaceutical composition with an antiproliferative activity.
- the invention relates to pharmaceutical preparations containing as active substance one or more compounds of general formula (1) or (IA), or the pharmaceutically effective salts thereof optionally in combination with conventional excipients and/or carriers.
- the invention relates to the use of compounds of general formula (1) or (IA) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
- the invention in another aspect relates to a pharmaceutical preparation
- a pharmaceutical preparation comprising a compound of general formula (1) or (IA) and at least one other antiproliferative active substance, different from formula (1) or (IA), optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmaceutically effective salts thereof.
- alkyl substituents are meant in each case saturated, unsaturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group) and this includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups.
- Alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups, which have at least one double bond.
- alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups, which have at least one triple bond.
- Heteroalkyl represents unbranched or branched aliphatic hydrocarbon chains which contain 1 to 3 heteroatoms, while each of the available carbon and heteroatoms in the heteroalkyl chain may optionally each be substituted independently and the heteroatoms independently of one another are selected from among O, N, P, PO, PO 2 , S, SO and SO 2 (e.g.
- dimethylaminomethyl dimethylaminoethyl, dimethylaminopropyl, diethylamino methyl, diethylamino ethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis- 2-methoxyethylamino, [2-(dimethylamino-ethyl)-ethyl-amino]-methyl, 3-[2- (dimethylamino-ethyl)-ethyl-amino]-propyl, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).
- Haloalkyl refers to alkyl groups wherein one or more hydrogen atoms are replaced by halogen atoms.
- Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.
- cycloalkyl a mono- or polycyclic ring, wherein the ring system may be a saturated ring but also an unsaturated, non-aromatic ring or a spiro compound, which may optionally also contain double bonds, such as for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, norbornyl, norbornenyl, indanyl, adamantyl, spiroheptanyl and spiro[4.2]heptanyl.
- Cycloalkylalkyl includes a non-cyclic alkyl as hereinbefore defined wherein a hydrogen atom bound to a carbon atom is replaced by a cycloalkyl group.
- Aryl relates to monocyclic or bicyclic rings with 6 - 12 carbon atoms such as for example phenyl and naphthyl.
- Arylalkyl includes a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom is replaced by an aryl group.
- heteroaryl mono- or polycyclic rings which contain, instead of one or more carbon atoms, one or more heteroatoms, which may be identical or different, such as e.g. nitrogen, sulphur or oxygen atoms.
- heteroatoms such as e.g. nitrogen, sulphur or oxygen atoms.
- Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.
- bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
- Heteroarylalkyl encompasses a non-cyclic alkyl wherein a hydrogen atom bound to a carbon atom is replaced by a heteroaryl group.
- Heterocycloalkyl relates to saturated or unsaturated, non-aromatic mono-, polycyclic or bridged polycyclic rings or spiro compounds comprising 3 - 12 carbon atoms, which carry heteroatoms, such as nitrogen, oxygen or sulphur, instead of one or more carbon atoms.
- heterocyclyl groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, ho mo thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl- ⁇ - dioxide, tetrahydropyranyl, tetrahydrothienyl, homothiomorpholinyl- ⁇ -dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl
- Heterocycloalkylalkyl relates to a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom is replaced by a heterocycloalkyl group.
- substituted is meant that a hydrogen atom which is bound directly to the atom in question is replaced by a different atom or a different atomic group.
- Step 1 The preparation of the intermediate compound III is carried out by substitution of a leaving group (LG), for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system I by a nucleophile II.
- LG leaving group
- the preparation of the end compound V is carried out by substitution of a leaving group LG, for example halogen, SCN or methoxy, preferably chlorine, in a heteroaromatic system III by a nucleophile IV.
- LG for example halogen, SCN or methoxy, preferably chlorine
- iv v 1 equivalent of the compound III and 1 - 3 equivalents of the compound IV are stirred in a solvent, for example 1,4-dioxane, DMF, DMA, 7V-methyl-2-pyrrolidinone or water.
- a solvent for example 1,4-dioxane, DMF, DMA, 7V-methyl-2-pyrrolidinone or water.
- an inorganic acid for example sulphuric acid or hydrochloric acid
- Step 3B molecules with a carbonyl group may be reacted with an amine.
- Molecules with an additional N atom may be reacted with an alkyl halide (alkyl-Hal).
- Vl XII XIII 1 equivalent of the compound VI and 1 - 10 equivalents of the compound XII are stirred in a solvent, for example 1,4-dioxane, THF, DMF or acetonitrile.
- a solvent for example 1,4-dioxane, THF, DMF or acetonitrile.
- 2 - 2.5 equivalents of a base for example potassium carbonate, sodium carbonate, caesium carbonate, ethyldiispropylamine or triethylamine.
- the reaction mixture is stirred for a further 12 - 72 h at a temperature of 15 - 25°C, then combined with water, which has been adjusted to a pH of 8 - 9 with an inorganic base, for example sodium hydrogen carbonate or potassium carbonate.
- Molecules that have a carboxyl group may be reacted with an amine. If the carboxyl group is present in a protected form it is converted into the deprotected compound beforehand by hydrolysis or similar methods known to the skilled man.
- 1 equivalent of the compound XIV, 1 - 1.5 equivalents of the compound X and 1 - 3 equivalents of a base are stirred in a solvent, for example 1,4-dioxane, DMF, DMA or 7V-methyl-2-pyrrolidinone.
- a base for example triethylamine or ethyldiisopropylamine
- a coupling reagent for example N, N- dicyclohexylcarbodiimide, 7V,7V-diisopropylcarbodiimide, O-(benzotriazol- 1 -y ⁇ )-N,N,N',N'- tetramethyluronium-tetrafluoroborate, 1 -(3 -N,7V-dimethylaminopropyl)-3 - ethylcarbodiimide or O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, are added.
- the reaction mixture is stirred for a further 4 - 24 h at a temperature of 15 - 25°C.
- the solvent is distilled off and the residue is purified by chromatography.
- Nagel Polygoprep 100-50 C 18 is used.
- the apparatus is constructed so that the chromatography (column: Zorbax SB-C8, 3.5 ⁇ m, 2.1*50, Agilent) is followed by a diode array detector (G1315B made by Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) connected in series. This apparatus is operated with a flow of 0.6 mL/min.
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water and 5% acetonitrile and at the finishing point of 70% water and 30% acetonitrile. 0.2 % formic acid is added to both eluants. The suitable fractions are freeze-dried. 140 mg of the intermediate product thus obtained are combined with 15 mL DMF, 8 mL water and 30 mg palladium hydroxide and hydrogenated for 2 h at 7 bar H 2 pressure. The catalyst is filtered off and the solvent is eliminated in vacuo. Yield: 0.47 g
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 85% water and 15% acetonitrile and at the finishing point of 5% water and 95% acetonitrile. 0.2% NH3/KHCO3 is added to both eluants. The suitable fractions are freeze-dried. Yield: 22 mg
- Example 53 The following compounds are prepared by a process analogous to that described in Example 53.
- the preparation of 2-chloro-4-(3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5- yl)-5-dimethylamino-pyrimidine is described in Example 63.
- Example 64 - 191 The following compounds are prepared by a process analogous to that described in Example 63.
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 80% water (10 mM ammonium hydrogen carbonate and 38 mM ammonia) and 20% acetonitrile and at the finishing point of 35% water and 65% acetonitrile. Fractions are freeze-dried. The residue is taken up in acetonitrile, combined with aqueous hydrochloric acid and freeze-dried again. Yield: 40 mg
- the following compounds are prepared by a process analogous to that described in Example 192.
- the acid component for Examples 228 to 232 may be obtained by saponification of the methyl ester (see Example 14).
- the carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 80% water (10 mM ammonium hydrogen carbonate and 20 mM ammonia) and 20% acetonitrile and at the finishing point of 35% water and 65% acetonitrile. The appropriate fractions are freeze-dried. The residue is taken up in acetonitrile, combined with aqueous hydrochloric acid and freeze-dried once again. Yield: 17.5 mg
- the effect of the compounds according to the invention on various kinases is determined in in vitro kinase assays with recombinantly prepared protein.
- the compounds in this assay exhibit good to very good activity, i.e. for example an IC 50 value of less than 1 ⁇ mol/L, generally less than 0.1 ⁇ mol/L.
- Recombinant human PDKl enzyme (aa 52-556) attached to HiS 6 at its N-terminal end is isolated from Baculovirus-infected insect cells. Purified enzyme may also be obtained for example through Upstate.
- the following components are combined in a well of a 96-well round-bottomed plate (Greiner bio-one, No. 650101):
- KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC synthesised by Pepceuticals Limited, Nottingham, United Kingdom; 25 ⁇ M final concentration; PDKl and PDKtide are correspondingly diluted together in assay buffer; PDKtide is present in this mixture as an 83.3 ⁇ M solution) - 10 ⁇ L ATP solution (25 ⁇ M ATP with 0.5 ⁇ Ci/well of gamma-P33-ATP)
- the reaction is started by adding the ATP solution and incubated for 30 min at RT; at the start of the reaction the plates are shaken gently. The reaction is stopped by the addition of 5 ⁇ L/well 0.5 M phosphoric acid (H3PO4) and incubated for about 20 min at RT. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H 3 PO 4 and dried at 6O 0 C. Then the plate is stuck down with sealing tape, 25 ⁇ L/well of scintillation solution (Microscint 0; Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measurement data are evaluated using the Standard Graphpad software.
- the antiproliferative activity of the compounds according to the invention is determined on cultivated human tumour cells, for example on PC-3 cells.
- the compounds exhibit good to very good activity, i.e. for example an EC50 value of less than 5 ⁇ mol/L, generally less than 1 ⁇ mol/L in the PC-3 proliferation test. Measurement of the inhibition of proliferation on cultivated human tumour cells
- cells of prostate carcinoma tumour cell line PC-3 are cultivated in Ham's F 12 Medium (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase.
- PC-3 cells are placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37°C and 5% CO2), while on each plate 16 wells are used as controls (8 wells with cells to which only DMSO solution has been added (should yield 30 - 50% maximum value of reduced AlamarBlue), 4 wells containing only medium (medium control, after the addition of oxidised AlamarBlue reagent the background signal is obtained) and 4 wells where again only medium is added (after the addition of reduced AlamarBlue reagent it acts as a maximum value)).
- the active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1% or 1%) (in each case as a double or triple measurement). After 5 days' incubation 20 ⁇ l AlamarBlue reagent (Serotec) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 ⁇ l reduced AlamarBlue reagent is added to each of 4 wells. After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a SpectraMax Photometer (Molecular Devices) (extinction 530 nm, emission 590 nm, 5 sec measuring time). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity is calculated in relation to the control (PC-3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (EC50) is derived. The values are calculated from the average of two or three individual measurements.
- the compounds according to the invention are also tested accordingly on other tumour cells.
- these compounds are effective on carcinomas of all kinds of tissue (e.g. gliomas (U87), sarcoma (e.g. MES-SA, SK-UT-IB), breast (MDA-MB468), colon (HCTl 16), lung (H460)) and could be used in indications of this kind, particularly in indications which have activating changes in the PI3K- AKT-PDKl signal pathway.
- This demonstrates the wide range of applications for the compounds according to the invention for the treatment of all kinds of tumour types.
- the new compounds of general formula (1) or (IA) the isomers and the physiologically acceptable salts thereof are therefore suitable for treating diseases characterised by excessive or abnormal cell proliferation.
- Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy).
- viral infections e.g. HIV and Kaposi's sarcoma
- inflammatory and autoimmune diseases e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and
- brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinom
- lymphosarcoma such as for example malignant lymphoma, Hodgkin's disease, non- Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supra-glottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, cho
- the new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state-of-the-art" compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
- radiotherapy or other "state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
- the compounds of general formula (1) or (IA) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
- Chemotherapeutic agents which may be administered in combination with the compounds according to the invention include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fiuoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g.
- hormones e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride,
- anastrozole anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane
- LHRH agonists and antagonists e.g. goserelin acetate, luprolide
- inhibitors of growth factors growth factors such as for example "platelet derived growth factor” and “hepatocyte growth factor”
- inhibitors are for example "growth factor” antibodies, “growth factor receptor” antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab
- antimetabolites e.g.
- antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5- fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g.
- cisplatin, oxaliplatin, carboplatin alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g.
- epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
- epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron
- chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, me
- Suitable preparations include for example tablets, capsules, suppositories, solutions, - particularly solutions for injection (s.c, Lv., i.m.) and infusion - elixirs, emulsions or dispersible powders.
- the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
- the doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert dilu
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core may also consist of a number of layers.
- the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- a sweetener such as saccharine, cyclamate, glycerol or sugar
- a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
- suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aid
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
- Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
- Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g.
- pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
- lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
- lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
- the preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
- the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
- lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
- the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- solutions of the active substances with suitable liquid carriers may be used.
- the dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and
- the finely ground active substance, lactose and some of the corn starch are mixed together.
- the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
- the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
- the mixture is compressed to produce tablets of suitable shape and size.
- the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
- the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
- the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
- the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
- the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07787138A EP2041132A2 (de) | 2006-07-06 | 2007-07-05 | Neue verbindungen |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06116748 | 2006-07-06 | ||
EP07787138A EP2041132A2 (de) | 2006-07-06 | 2007-07-05 | Neue verbindungen |
PCT/EP2007/056853 WO2008003766A2 (en) | 2006-07-06 | 2007-07-05 | 4-heter0cycl0alkylpyri(mi)dines, process for the preparation thereof and their use as medicaments |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2041132A2 true EP2041132A2 (de) | 2009-04-01 |
Family
ID=37801393
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07787138A Withdrawn EP2041132A2 (de) | 2006-07-06 | 2007-07-05 | Neue verbindungen |
Country Status (5)
Country | Link |
---|---|
US (1) | US8258129B2 (de) |
EP (1) | EP2041132A2 (de) |
JP (1) | JP2009542604A (de) |
CA (1) | CA2654670A1 (de) |
WO (1) | WO2008003766A2 (de) |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2633318T3 (es) | 2006-10-23 | 2017-09-20 | Cephalon, Inc. | Derivados bicíclicos fusionados de 2,4-diaminopirimidina como inhibidores de ALK y c-Met |
JP5464709B2 (ja) | 2007-06-08 | 2014-04-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ピペリジン/ピペラジン誘導体 |
EP2152271B1 (de) | 2007-06-08 | 2015-10-21 | Janssen Pharmaceutica, N.V. | Piperidin-/piperazinderivate |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
AR066911A1 (es) | 2007-06-08 | 2009-09-23 | Janssen Pharmaceutica Nv | Derivados de piperidina / piperazina |
NZ587589A (en) * | 2008-02-15 | 2012-10-26 | Rigel Pharmaceuticals Inc | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
US20100056524A1 (en) * | 2008-04-02 | 2010-03-04 | Mciver Edward Giles | Compound |
PT2323993E (pt) | 2008-04-16 | 2015-10-12 | Portola Pharm Inc | 2,6-diamino-pirimidina-5-il-carboxamidas como inibidores de quinasses syk ou jak |
US8138339B2 (en) * | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
EP2296659B1 (de) | 2008-06-05 | 2016-12-21 | Janssen Pharmaceutica, N.V. | Einen DGAT-Inhibitor und einen PPAR-Agonisten enthaltende Arzneikombinationen |
UY31984A (es) * | 2008-07-16 | 2010-02-26 | Boehringer Ingelheim Int | DERIVADOS DE 1-(3,4-difluorobencil)-6-oxo-1,6-dihidropirimidin-5-carboxamidas N-sustituidas y de 2-(3,4-difluorobencil)-3-oxo-2,3-dihidro-1H-pirazol-4-carboxamidas N-sustituidas. |
US8933227B2 (en) | 2009-08-14 | 2015-01-13 | Boehringer Ingelheim International Gmbh | Selective synthesis of functionalized pyrimidines |
WO2011018517A1 (en) | 2009-08-14 | 2011-02-17 | Boehringer Ingelheim International Gmbh | Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives |
AR077999A1 (es) | 2009-09-02 | 2011-10-05 | Vifor Int Ag | Antagonistas de pirimidin y triazin-hepcidina |
ES2385276B1 (es) * | 2010-02-25 | 2013-07-05 | Universidad Del País Vasco | Compuestos para el tratamiento de alzheimer. |
ES2577829T3 (es) * | 2010-06-04 | 2016-07-19 | F. Hoffmann-La Roche Ag | Derivados de aminopirimidina como moduladores de la LRRK2 |
US8754114B2 (en) | 2010-12-22 | 2014-06-17 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
IN2014CN04065A (de) | 2011-11-23 | 2015-09-04 | Portola Pharm Inc | |
LT3176170T (lt) | 2012-06-13 | 2019-04-25 | Incyte Holdings Corporation | Pakeisti tricikliniai junginiai, kaip fgfr inhibitoriai |
WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
DK2986610T5 (en) | 2013-04-19 | 2018-12-10 | Incyte Holdings Corp | BICYCLIC HETEROCYCLES AS FGFR INHIBITORS |
EP3177597B1 (de) | 2014-07-31 | 2020-03-11 | Institut Pasteur Korea | 2-amino-benzimidazol-derivate als 5-lipoxygenase und/oder prostaglandin e synthase inhibitoren zur behandlung von entzündlichen erkrankungen |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
CN107438607B (zh) | 2015-02-20 | 2021-02-05 | 因赛特公司 | 作为fgfr抑制剂的双环杂环 |
ES2806206T3 (es) | 2015-03-11 | 2021-02-16 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Derivado de 2-hidrógeno pirazol sustituido que sirve como fármaco anticanceroso |
CN105111191B (zh) * | 2015-07-21 | 2018-06-08 | 上海皓元生物医药科技有限公司 | 一种用于合成cdk9抑制剂的关键中间体及其制备方法和用途 |
KR20180063895A (ko) | 2015-10-21 | 2018-06-12 | 오츠카 세이야쿠 가부시키가이샤 | 단백질 키나제 억제제로서의 벤조락탐 화합물 |
CN106928219B (zh) | 2015-12-31 | 2021-08-20 | 上海医药集团股份有限公司 | 含氮稠杂环化合物、制备方法、中间体、组合物和应用 |
CN108602799B (zh) * | 2016-02-06 | 2021-08-03 | 上海复尚慧创医药研究有限公司 | 一类激酶抑制剂 |
GB201706327D0 (en) | 2017-04-20 | 2017-06-07 | Otsuka Pharma Co Ltd | A pharmaceutical compound |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
CN107382974B (zh) * | 2017-06-08 | 2020-06-05 | 扬州市三药制药有限公司 | 一种嘧啶胺类化合物作为周期蛋白依赖性激酶4/6抑制剂的应用 |
WO2019090198A1 (en) * | 2017-11-06 | 2019-05-09 | Bristol-Myers Squibb Company | Isofuranone compounds useful as hpk1 inhibitors |
PE20210920A1 (es) | 2018-05-04 | 2021-05-19 | Incyte Corp | Formas solidas de un inhibidor de fgfr y procesos para prepararlas |
WO2019213506A1 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Salts of an fgfr inhibitor |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
CA3138973A1 (en) * | 2019-05-05 | 2020-11-12 | Qilu Regor Therapeutics Inc. | Cdk inhibitors |
CN114555585A (zh) * | 2019-07-04 | 2022-05-27 | 上海齐鲁锐格医药研发有限公司 | Hpk1抑制剂及其用途 |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
KR20220100879A (ko) | 2019-10-14 | 2022-07-18 | 인사이트 코포레이션 | Fgfr 저해제로서의 이환식 헤테로사이클 |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
PE20221504A1 (es) | 2019-12-04 | 2022-09-30 | Incyte Corp | Derivados de un inhibidor de fgfr |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
WO2023164234A1 (en) | 2022-02-28 | 2023-08-31 | Agios Pharmaceuticals, Inc. | Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations |
WO2023164235A1 (en) | 2022-02-28 | 2023-08-31 | Agios Pharmaceuticals, Inc. | Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations |
WO2023164233A1 (en) | 2022-02-28 | 2023-08-31 | Agios Pharmaceuticals, Inc. | (4-benzo[d]oxazol-2-yl)-6,7-dihydro-1h-imidazo[4,5-c]pyridine-5(4h)-yl)methanone derivatives as mutant pah stabilizers for the treatment of phenylketonuria |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5935966A (en) * | 1995-09-01 | 1999-08-10 | Signal Pharmaceuticals, Inc. | Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions |
AU726058B2 (en) * | 1995-09-01 | 2000-10-26 | Signal Pharmaceuticals, Inc. | Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions |
GB9905075D0 (en) * | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
GB9914258D0 (en) * | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
GB9919778D0 (en) * | 1999-08-21 | 1999-10-27 | Zeneca Ltd | Chemical compounds |
EP1423388B1 (de) * | 2001-02-20 | 2008-12-03 | AstraZeneca AB | 2-arylaminopyrimidine zur behandlung von mit gsk3 in zusammenhang stehenden erkrankungen |
WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
CA2463989C (en) * | 2001-10-17 | 2012-01-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pyrimidine derivatives, pharmaceutical compositions containing these compounds, the use thereof and process for the preparation thereof |
GB0308466D0 (en) * | 2003-04-11 | 2003-05-21 | Novartis Ag | Organic compounds |
WO2005111024A1 (en) * | 2004-05-14 | 2005-11-24 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
WO2006038001A1 (en) * | 2004-10-06 | 2006-04-13 | Celltech R & D Limited | Aminopyrimidine derivatives as jnk inhibitors |
US20060161001A1 (en) * | 2004-12-20 | 2006-07-20 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
ATE430747T1 (de) * | 2004-12-21 | 2009-05-15 | Smithkline Beecham Corp | 2-pyrimidinyl-pyrazolopyridin-erbb- kinaseinhibitoren |
JP5103403B2 (ja) * | 2005-12-05 | 2012-12-19 | スミスクライン ビーチャム コーポレーション | 2−ピリミジニルピラゾロピリジンErbBキナーゼ阻害剤 |
EP1966207A2 (de) * | 2005-12-21 | 2008-09-10 | Pfizer Products Inc. | Pyrimidinderivate zur behandlung von anormalem zellwachstum |
AU2007261440A1 (en) * | 2006-06-22 | 2007-12-27 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
CA2672639A1 (en) * | 2006-12-22 | 2008-07-03 | Novartis Ag | Indol-4-yl-pyrimidinyl-2-yl-amine derivatives and use thereof as cyclin dependant kinase inhibitors |
-
2007
- 2007-07-05 EP EP07787138A patent/EP2041132A2/de not_active Withdrawn
- 2007-07-05 CA CA002654670A patent/CA2654670A1/en not_active Abandoned
- 2007-07-05 JP JP2009517280A patent/JP2009542604A/ja not_active Ceased
- 2007-07-05 US US12/304,134 patent/US8258129B2/en active Active
- 2007-07-05 WO PCT/EP2007/056853 patent/WO2008003766A2/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2008003766A2 * |
Also Published As
Publication number | Publication date |
---|---|
JP2009542604A (ja) | 2009-12-03 |
WO2008003766A2 (en) | 2008-01-10 |
WO2008003766A3 (en) | 2008-02-28 |
US20090203673A1 (en) | 2009-08-13 |
US8258129B2 (en) | 2012-09-04 |
CA2654670A1 (en) | 2008-01-10 |
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